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Results for “Cannabinoid Receptor Modulators”

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PubMed2003

Cannabinoid receptor type 1 modulates excitatory and inhibitory neurotransmission in mouse colon.

The effects of cannabinoid receptor agonists and antagonists on smooth muscle resting membrane potentials and on membrane potentials following electrical neuronal stimulation in a myenteric neuron/smooth muscle preparation of wild-type and cannabinoid receptor type 1 (CB1)-deficient mice were investigated in vitro. Double staining for CB1 and nitric oxide synthase (neuronal) was performed to identify the myenteric CB1-expressing neurons. Focal electrical stimulation of the myenteric plexus induced a fast (f) excitatory junction potential (EJP) followed by a fast and a slow (s) inhibitory junction potential (IJP). Treatment of wild-type mice with the endogenous CB1 receptor agonist anandamide reduced EJP while not affecting fIJP and sIJP. EJP was significantly higher in CB1-deficient mice than in wild-type littermate controls, and anandamide induced no effects in CB1-deficient mice. N-arachidonoyl ethanolamide (anandamide), R-[2,3-dihydro-5-methyl-3-(4-morpholinylmethyl)pyrrolo[1,2,3,-de]- 1,4-benzoxazin-6-yl]-1-naphtalenylmethanone, a synthetic CB1 receptor agonist, nearly abolished EJP and significantly reduced the fIJP in wild-type mice. N-piperidino-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-3-pyrazole-caroxamide (SR141716A), a CB1-specific receptor antagonist, was able to reverse the agonist effects induced in wild-type mice. SR141716A, when given alone, significantly increased EJP in wild-type mice without affecting IJP in wild-type and EJP in CB1-deficient mice. Interestingly, SR141716A reduced fIJP in CB1-deficient mice. In the mouse colon, nitrergic myenteric neurons do not express CB1, implying that CB1 is expressed in cholinergic neurons, which is in line with the functional data. Finally, excitatory and inhibitory neurotransmission in the mouse colon is modulated by activation of CB1 receptors. The significant increase in EJP in CB1-deficient mice strongly suggests a physiological involvement of CB1 in excitatory cholinergic neurotransmission.

Animals↗
PubMedDate not supplied

Cardiovascular actions of cannabinoids and their generation during shock.

Marijuana is a widely abused recreational drug well known for its psychoactive properties. Cannabinoids, the active ingredients of marijuana, elicit their neurobehavioral effects by interacting with the CB1 cannabinoid receptor subtype, expressed primarily in the brain but also present in some peripheral tissues. A second receptor subtype, the CB2 receptor, is expressed on cells of the immune system and is thought to be responsible for the immunosuppressant effects of cannabinoids. Recently, endogenous lipidlike substances have been identified, including arachidonyl ethanolamide (anandamide) and 2-arachidonyl glyceride, that bind to cannabinoid receptors and mimic many of the neurobehavioral effects of plant-derived cannabinoids. Both plant-derived cannabinoids and the endogenous ligands have been shown to elicit hypotension and bradycardia via activation of peripherally located CB1 receptors. Possible underlying mechanisms include presynaptic CB1 receptor mediated inhibition of norepinephrine release from peripheral sympathetic nerve terminals, and/or direct vasodilation via activation of vascular cannabinoid receptors. The latter may also be the target of endocannabinoids of vascular endothelial origin. Recent studies indicate that a peripheral endogenous cannabinoid system in circulating macrophages and platelets is activated in hemorrhagic and septic shock and may contribute to the hypotension associated with these conditions via activation of vascular cannabinoid receptors. The potential role of this mechanism in human shock conditions is under investigation.

Animals↗
PubMed2000

The endogenous cannabinoid system and brain development.

Cannabinoid receptors and their endogenous ligands constitute a novel modulatory system that is involved in specific brain functions, such as nociception, control of movement, memory and neuroendocrine regulation. Recently, it has also been suggested that this system is involved in brain development. Studies have used a variety of techniques to elucidate the effects of cannabinoids during development, as well as to characterize the presence of elements of the endogenous cannabinoid system (receptors and ligands) in the developing brain. Collectively, they suggest that endocannabinoids participate in brain development through the activation of second-messenger-coupled cannabinoid receptors.

Animals↗
PubMed2001

The role of cannabinoids in neurodegenerative diseases.

An understanding of the actions of Cannabis (Marijuana) has evolved from folklore to science over the previous hundred years. This progression was spurred by the discovery of an endogenous cannabinoid system consisting of two receptors and two endogenous ligands. This system appears to be intricately involved in normal physiology, specifically in the control of movement, formation of memories and appetite control. As we are developing an increased understanding of the physiological role of endocannabinoids it is becoming clear that they may be involved in the pathology of several neurological diseases. Furthermore an array of potential therapeutic targets is being determined--including specific cannabinoid agonists and antagonists as well as compounds that interrupt the synthesis, uptake or metabolism of the endocannabinoids. This article reviews the recent progress in understanding the contribution of endocannabinoids to the pathology and therapy of Huntington's disease. Parkinson's disease, schizophrenia and tremor.

Animals↗
PubMed2002

Endocannabinoids and cannabinoid receptor genetics.

This review presents the remarkable advances that have been achieved in marijuana (cannabinoid) research, with the discovery of specific receptors and the existence of naturally occurring cannabis-like substances in the human body and brain. The last decade has seen more rapid progress in marijuana research than any time in the thousands of years that marijuana has been used by humans, particularly in cannabinoid genomics. The cDNA and genomic sequences encoding G protein-coupled cannabinoid receptors (Cnrs) from several species have now been cloned. Endogenous cannabinoids (endocannabinoids), synthetic and hydrolyzing enzymes and transporters that define neurochemically-specific cannabinoid brain pathways have been identified. Endocannabinoid lipid signaling molecules alter activity at G protein-coupled receptors (GPCR) and possibly at anandamide-gated ion channels, such as vanilloid receptors. Availability of increasingly-specific CB1 and CB2 Cnr antagonists and of CB1 and CB2 Cnr knockout mice have increased our understanding of these cannabinoid systems and provides tantalizing evidence for even more G protein-coupled Cnrs. Initial studies of the Cnr gene structure, regulation and polymorphisms whet our appetite for more information about these interesting genes, their variants and roles in vulnerabilities to addictions and other neuropsychiatric disorders. Behavioral studies of cannabinoids document the complex interactions between rewarding and aversive effects of these drugs. Pursuing cannabinoid-related molecular, pharmacological and behavioral leads will add greatly to our understanding of endogenous brain neuromodulator systems, abused substances and potential therapeutics. This review of CB1 and CB2 Cnr genes in human and animal brain and their neurobiological effects provide a basis for many of these studies. Therefore, understanding the physiological cannabinoid control system in the human body and brain will contribute to elucidating this natural regulatory mechanism in health and disease.

Amino Acid Sequence↗
PubMed2002

Retrograde signaling by endocannabinoids.

Recent studies suggest that endocannabinoids act as retrograde messengers at many synapses in the central nervous system. Activation of phospholipases, either through calcium-mediated or receptor-mediated signaling, leads to the formation and release of endocannabinoids. These lipophilic signaling molecules diffuse to nearby presynaptic terminals where they bind to specific G-protein-coupled receptors and inhibit neurotransmitter release for tens of seconds. Thus, an important physiological role of endocannabinoids may be to provide a mechanism by which neurons can rapidly regulate the strength of their synaptic inputs.

Animals↗
PubMed2001

Novel physiologic functions of endocannabinoids as revealed through the use of mutant mice.

The presence in the mammalian brain of specific receptors for marijuana triggered a search for endogenous ligands, several of which have been recently identified. There has been growing interest in the possible physiological functions of endocannabinoids, and mutant mice that lack cannabinoid receptors have become an important tool in the search for such functions. To date, studies using CB1 knockout mice have supported the possible role of endocannabinoids in retrograde synaptic inhibition in the hippocampus, in long-term potentiation and memory, in the development of opiate dependence, and in the control of appetite and food intake. They also suggested the existence of as yet unidentified cannabinoid receptors in the cardiovascular and central nervous systems. The use of CB2 receptor knockout mice suggested a role for this receptor in macrophage-mediated helper T cell activation. Further studies will undoubtedly reveal many additional roles for this novel signaling system.

Animals↗
PubMed2006

Endocannabinoid overactivity and intestinal inflammation.

Cannabinoid receptors of type 1 and 2 (CB(1) and CB(2)), endogenous ligands that activate them (endocannabinoids), and mechanisms for endocannabinoid biosynthesis and inactivation have been identified in the gastrointestinal system. Activation of CB(1 )receptors by endocannabinoids produces relaxation of the lower oesophageal sphincter and inhibition of gastric acid secretion, intestinal motility, and fluid stimulated secretion. However, stimulation of cannabinoid receptors impacts on gastrointestinal functions in several other ways. Recent data indicate that the endocannabinoid system in the small intestine and colon becomes over stimulated during inflammation in both animal models and human inflammatory disorders. The pathological significance of this "endocannabinoid overactivity" and its possible exploitation for therapeutic purposes are discussed here.

Cannabinoid Receptor Modulators↗
PubMed2000

Cannabinoid receptor ligands: clinical and neuropharmacological considerations, relevant to future drug discovery and development.

This review highlights some important advances that have taken place in cannabinoid research over the last four years. It focuses on novel ligands that are of interest either as experimental tools or as lead compounds for therapeutic agents and possible clinical applications for some of these ligands. The molecular targets for these compounds are various components of the system of endogenous cannabinoids (endocannabinoids) and receptors that together constitute the 'endocannabinoid system'. These are CB(1) cannabinoid receptors that are present mainly on central and peripheral neurones, CB(2) cannabinoid receptors that are expressed predominantly by immune cells, the biochemical mechanisms responsible for the tissue uptake or metabolism of endocannabinoids and vanilloid receptors. Other cannabinoid receptor types may also exist. Recently developed ligands include potent and selective agonists for CB(1) and CB(2) receptors, a potent CB(2)-selective antagonist/inverse agonist and inhibitors of endocannabinoid uptake or metabolism. Future research should be directed at characterising the endocannabinoid system more completely and at obtaining more conclusive clinical data about the possible beneficial effects of cannabinoids as well as their adverse effects. There is also a need for improved cannabinoid formulations/modes of administration in the clinic and advances in this area should be facilitated by the recent development of a potent water-soluble CB(1)/CB(2) receptor agonist. A growing number of strategies for separating sought-after therapeutic effects of cannabinoid receptor agonists from the unwanted consequences of CB(1) receptor activation are now emerging and these are discussed at the end of this review.

Animals↗
PubMed2005

Cannabinoids and the regulation of ingestive behaviour.

Over past centuries, Cannabis sativa (Delta(9)-tetrahydrocannabinol being the principal active ingredient) has been used extensively for both medicinal and recreational uses, and one widely reported effect is the onset of a ravenous appetite and eating behaviour. The pharmacological properties of such exogenous cannabinoids are mediated through the activation of two receptor subtypes, the CB(1) and CB(2) receptors. A number of endogenous ligands for these receptors, the endocannabinoids, have now also been identified allowing their effects on ingestive behaviour to be determined. In a number of species, including man, the administration of exogenous and endogenous cannabinoids leads to robust increases in food intake and can promote body weight gain. These effects are believed to be mediated through activation of the CB(1) receptor. Conversely, experiments with selective CB(1) receptor antagonists have demonstrated reductions in food intake and body weight with repeated compound administration. These reductions in body weight appear to be greater in obese animals and may be the result of a dual effect on both food intake and metabolic processes. Such findings have led to a number of pharmaceutical companies developing selective CB(1) receptor antagonists for the treatment of obesity. The most advanced compound is Sanofi-Synthelabo's inverse agonist, rimonabant (Acomplia; SR-141716), and early Phase III results have recently demonstrated significant reductions in body weight, waist circumference and improvement of lipid and glucose metabolism in overweight and obese humans. Accordingly, the cannabinoid system appears to have an important role in the regulation of ingestive behaviour in man and animals.

Animals↗
PubMed2006

The endogenous cardiac cannabinoid system: a new protective mechanism against myocardial ischemia.

The pharmacological (and recreational) effects of cannabis have been known for centuries. However, it is only recently that one has identified two subtypes of G-protein-coupled receptors, namely CB1 and CB2-receptors, which mediate the numerous effects of delta9-tetrahydrocannabinol and other cannabinoids. Logically, the existence of cannabinoid-receptors implies that endogenous ligands for these receptors (endocannabinoids) exist and exert a physiological role. Hence, arachidonoylethanolamide (anandamide) and sn-2 arachidonoylglycerol, the first two endocannabinoids identified, are formed from plasma membrane phospholipids and act as CB1 and/or CB2 agonists. The presence of both CB1 and CB2-receptors in the rat heart is noteworthy. This endogenous cardiac cannabinoid system is involved in several phenomena associated with cardioprotective effects. The reduction in infarct size following myocardial ischemia, observed in rats exposed to either LPS or heat stress 24 hours before, is abolished in the presence of a CB2-receptor antagonist. Endocannabinoids and synthetic cannabinoids, the latter through either CB1 or CB2-receptors, exert direct cardioprotective effects in rat isolated hearts. The ability of cannabinoids to reduce infarct size has been confirmed in vivo in anesthetized mice and rats. This latter effect appears to be mediated through CB2-receptors. Thus, the endogenous cardiac cannabinoid system, through activation of CB2-receptors, appears to be an important mechanism of protection against myocardial ischemia.

Animals↗
PubMed1998

2-Arachidonoyl-glycerol as an "endocannabinoid": limelight for a formerly neglected metabolite.

Previously believed to simply be an intermediate in tri- and diglyceride metabolism or an alternative precursor for arachidonic acid, 2-arachidonoyl-glycerol has lately attracted renewed interest from lipid biochemists and pharmacologists. This is due to the finding of its cannabimimetic activity. In the present article recent landmarks that have led to the proposition of a role of this monoglyceride as an "endocannabinoid", starting from its newly discovered pharmacological properties in both central and peripheral tissues and ending with studies on the possible biosynthetic pathways for its formation, are reviewed. Also considered are possible interactions with another arachidonic acid-derived endogenous cannabinoid, anandamide.

Animals↗
PubMed2005

The use of cannabinoids in multiple sclerosis.

Naturally occurring cannabinoids including Delta9-tetrahydrocannabinol and cannabidiol as well as endocannabinoids and synthetic cannabinoids may have a role in modulating experimental models of multiple sclerosis. Recent clinical studies to treat symptoms of multiple sclerosis have shown varying results, which may reflect issues relating to the way in which such studies were conducted. There is now increasing interest in the potential role of cannabinoids not only in symptom relief, but also for their possible neuroprotective actions.

Animals↗
PubMed2006

Cannabinoid CB1 receptor antagonism modulates plasma corticosterone in rodents.

Although the involvement of cannabinoids and the endogenous cannabinoid system in the regulation of the hypothalamo-pituitary-adrenal axis in rodents is well documented, the precise role played by the cannabinoid type one (CB(1)) receptor in this effect has not been fully elucidated. Consequently, we investigated the role of CB(1) receptor in modulating plasma corticosterone concentrations through use of the potent and selective CB(1) receptor antagonist SR141716A and CB(1) receptor knockout mice. Rats were administered SR141716A (0.1, 0.3, and 1 mg/kg, i.v.) and blood was sampled at 0, 15, 60, 90 and 120 min postinjection. SR141716A dose- and time-dependently increased plasma corticosterone levels and maximum effects were obtained with the 1 mg/kg dose 60 min postinjection. In mice, SR141716A (0.1, 0.3, 1, 3, and 10 mg/kg, i.p.) also induced a dose-dependent rise in corticosterone levels 60 min postinjection; this rise reached plateau levels with the 0.3-1 mg/kg doses. The stimulatory effect of SR141716A (1 mg/kg, i.p.) on plasma corticosterone 60 min postinjection was abolished in the CB(1) receptor knockout mice, which did not show any difference in basal corticosterone levels as compared to their wild-type controls. Finally, the stimulatory effects of SR141716A (10 mg/kg, i.p.) on plasma corticosterone 60 min postinjection were retained after subchronic dosing (5 days, once daily) in mice. The present results indicate that SR141716A increases plasma corticosterone in rats and mice possibly through blockade of CB(1) receptors, an effect that is retained after subchronic dosing in mice. These data provide support for the notion that changes in plasma corticosterone concentrations may be used in the laboratory and the clinic to assess the effects of CB(1) receptor antagonism.

Animals↗
PubMedDate not supplied

Endocannabinoids in pain modulation.

Five major approaches have been employed to determine the role of endocannabinoids in pain modulation: (1) studies of various markers of endocannabinoid action aimed at determining whether the necessary cannabinoid biochemical machinery is present in those brain areas that control pain sensitivity; (2) administration of exogenous cannabinoids to determine whether endocannabinoid action at appropriate sites would lead to a loss of pain sensitivity; (3) administration of compounds that would affect endocannabinoid action such as antagonists and transport inhibitors to determine whether drug-induced preterbation of cannabinoid action would alter pain sensitivity; (4) studies of genetically altered animals aimed at determining whether pain responses or responses to cannabinergic drugs are altered; and (5) studies that measure the release of endocannabinoids. Converging evidence from each of these research areas indicates that endocannabinods function to control pain in parallel with endogenous opioids but via different mechanisms.

Animals↗
PubMed2002

Cannabinoids inhibit striatonigral GABAergic neurotransmission in the mouse.

The substantia nigra pars reticulata (SNR) belongs to the brain regions with the highest density of CB(1) cannabinoid receptors. Anatomical studies indicate that the great majority of CB(1) receptors in the SNR are localized on terminals of GABAergic axons arriving from the caudate-putamen (striatonigral axons). The aim of the present experiments was to clarify the role of CB(1) receptors on terminals of striatonigral axons. Oblique sagittal slices, including the caudate-putamen and the substantia nigra, were prepared from brains of young mice. Electrical stimulation in the caudate-putamen elicited GABAergic inhibitory postsynaptic currents (IPSCs) in the SNR, which were studied by patch-clamp techniques. The long latency of IPSCs (14+/-1 ms) suggests that striatonigral axons were indeed activated within the caudate-putamen. The synthetic CB(1)/CB(2) cannabinoid receptor agonist WIN55212-2 (R(+)-[2,3-dihydro-5-methyl-3-[(morpholinyl)methyl]pyrrolo[1,2,3-de]-1,4-benzoxazin-yl]-(1-naphthalenyl)methanone mesylate; 10(-5) M) decreased the amplitude of IPSCs by 93+/-1%. CP55940 ((-)-cis-3-[2-hydroxy-4-(1,1-dimethylheptyl)phenyl]-trans-4-(3-hydroxypropyl)cyclohexanol; 10(-5) M), another CB(1)/CB(2) receptor agonist, also reduced IPSC amplitude, by 76+/-4%. The CB(1) cannabinoid receptor antagonist SR141716A (N-piperidino-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-3-pyrazole-carboxamide; 10(-6) M) prevented the inhibition produced by WIN55212-2 (10(-5) M). Depolarization of SNR neurons led to suppression of IPSCs; this suppression was prevented by SR141716A (10(-6) M). Three observations indicate that the agonists inhibited neurotransmission presynaptically. (1) CP55940 (10(-5) M) enhanced the ratio of amplitudes of two IPSCs which were elicited by two electrical stimuli 100 ms apart (paired pulses). (2) WIN55212-2 (10(-5) M) did not change the amplitude of miniature IPSCs recorded in the presence of tetrodotoxin. (3) WIN55212-2 (10(-5) M) also had no effect on currents elicited in SNR neurons by ejection of the GABA(A) receptor agonist muscimol from a pipet. In summary, we have established a method which allows selective examination of GABAergic neurotransmission between striatonigral axons and SNR neurons. Using this method, the function of CB(1) cannabinoid receptors on terminals of striatonigral axons was unequivocally clarified. Activation of these receptors causes strong presynaptic inhibition of GABAergic neurotransmission between striatonigral axons and SNR neurons. This effect may be one explanation of the catalepsy observed in animals after cannabinoid administration. Endocannabinoids released from SNR neurons can modulate striatonigral neurotransmission by inhibiting GABA release from terminals of striatonigral axons.

Animals↗